title: Crystallographic Investigation and Selective Inhibition of Mutant Isocitrate Dehydrogenase.
abstract: Mutations in isocitrate dehydrogenase (IDH), a key enzyme in the tricarboxylic acid cycle, have recently been found in ~75% glioma and ~20% acute myeloid leukemia. Different from the wild-type enzyme, mutant IDH1 catalyzes the reduction of α-ketoglutaric acid toD-2-hydroxyglutaric acid. Strong evidence has shown mutant IDH1 represents a novel target for this type of cancer. We found two 1-hydroxypyridin-2-one compounds that are potent inhibitors of R132H and R132C IDH1 mutants with Kivalues as low as 120 nM. These compounds exhibit >60-fold selectivity against wild-type IDH1 and can inhibit the production ofD-2-hydroxyglutaric acid in IDH1 mutated cells, representing novel chemical probes for cancer biology studies. We also report the first inhibitor-bound crystal structures of IDH1(R132H), showing these inhibitors have H-bond, electrostatic and hydrophobic interactions with the mutant enzyme. Comparison with the substrate-bound IDH1 structures revealed the structural basis for the high enzyme selectivity of these compounds.
authors.affiliation: Department of Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas 77030, United States.
authors.forename: Baisong
authors.initials: B
authors.lastname: Zheng
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yao
authors.forename: Zhen
authors.initials: Z
authors.lastname: Liu
authors.forename: Lisheng
authors.initials: L
authors.lastname: Deng
authors.forename: Justin L
authors.initials: JL
authors.lastname: Anglin
authors.forename: Hong
authors.initials: H
authors.lastname: Jiang
authors.forename: B V Venkataram
authors.initials: BV
authors.lastname: Prasad
authors.forename: Yongcheng
authors.initials: Y
authors.lastname: Song
keywords: Enzyme inhibition; Gene mutation; isocitrate dehydrogenase; protein crystallography